Current Cancer Drug Targets - Volume 23, Issue 11, 2023

Background: Neuroblastoma is one of the most common childhood solid tumors. Because tumor suppressor genes are often hypermethylated in cancers, DNA methylation has emerged as a target for cancer therapeutics. Nanaomycin A, an inhibitor of DNA methyltransferase 3B, which mediates de novo DNA methylation, reportedly induces death in several types of human cancer cells. Objective: To study the antitumor activity of nanaomycin A against neuroblastoma cell lines and its mechanism. Methods: The anti-tumor effect of nanaomycin A on neuroblastoma cell lines was evaluated based on cell viability, DNA methylation levels, apoptosis-related protein expression, and neuronal-associated mRNA expression. Results: Nanaomycin A decreased genomic DNA methylation levels and induced apoptosis in human neuroblastoma cells. Nanaomycin A also upregulated the expression of mRNAs for several genes related to neuronal maturation. Conclusions: Nanaomycin A is an effective therapeutic candidate for treating neuroblastoma. Our findings also suggest that the inhibition of DNA methylation is a promising anti-tumor therapy strategy for neuroblastoma.

Cervical cancer is a common death-causing cancer among women in developing countries. Majority of the cases are triggered by persistent infections with high-risk Human Papillomavirus (HPV16 and 18). Metastasis, disease relapse, and drug resistance are common among patients in advanced stages of cancer despite the available therapies. Consequently, new prospective targets are needed for this disease. Autophagy is professed to have implications in cervical cancer progression as well as cancer dormancy. This article reviews the role of autophagy in cervical cancer progression and the modulation of the autophagy pathway by HPV. Further, various therapeutic agents that target autophagy in cervical cancer are discussed.

Testicular germ cell tumors (TGCT) are the leading cause of cancer-related death in young males between the ages of 20-40. Surgical resection and cisplatin-based chemotherapy can achieve a cure for the majority of patients with TGCTs, with survival rates of up to 97% for patients diagnosed at an early stage. The use of serum biomarkers, such as AFP β-HCG, and LDH, plays a significant role in both diagnosis and evaluation of response to treatment, and despite their low sensitivity and specificity levels, they are an integral part of the current tumor staging system and daily practice. Molecular biomarkers, including micro-RNAs and gene-expression profiles, are currently being developed in TGCTs and could potentially hold a prominent place in the future diagnosis, treatment selection, surveillance, and prognostication of these tumors. This review discusses how current advances in our understanding of the underlying biology of TGCTs have helped biomarker discovery, with a focus on the recognition of key molecular alterations that could serve as potential indicators of disease onset, response to systemic or/and surgical therapies, and overall clinical course.

Natural killer (NK) cell behavior and function are controlled by a balance between negative or positive signals generated by an extensive array of activating and inhibiting receptors, including killer cell immunoglobulin-like receptor (KIR) proteins, main components of the innate immune system that contribute to initial responses against viral infected-transformed cells through generation of the release of cytokines and cytotoxicity. What is certain is that KIRs are genetically polymorphic and the extent of KIRs diversity within the individuals may have the potential outcomes for hematopoietic stem cell transplantation (HSCT). In this regard, recent studies suggest that KIR is as imperative as its ligand (HLA) in stem cell transplantation for malignant diseases. However, unlike HLA epitope mismatches, which are well-known causes of NK alloreactivity, a complete understanding of KIR genes' role in HSCT remains unclear. Because of genetic variability in KIR gene content, allelic polymorphism, and cell-surface expression among individuals, an appropriate selection of donors based on HLA and KIR profiles is crucial to improve outcomes of stem cell transplantation. In addition, the impact of the KIR/HLA interaction on HSCT outcomes needs to be investigated more comprehensively. The present work aimed to review the NK cell regeneration, KIR gene polymorphisms, and KIRligand binding on outcomes in hematologic malignancies following haploidentical stem cell transplantation. Comprehensive data gathered from the literature can provide new insight into the significance of KIR matching status in transplantations.

One of the most important health problems in the world today is cancer. The World Health Organization (WHO) reported that it results in 8.9 million deaths annually. Malignant tumours and unregulated cell proliferation are features of malignant neoplasms, which can also invade nearby body regions. Hepatocellular carcinoma is the third most prevalent cause of cancer-related death worldwide and the fifth most common kind of cancer, according to a recent analysis. Patients with liver disease as well as chronic hepatitis B and C are more likely to develop hepatocellular carcinoma (HCC). Physical barriers, including RES absorption, opsonization, and first-pass drug metabolism, make drug therapy more challenging. Conventional cancer therapy procedures have a low response rate or may continue to be unsuccessful due to multi-drug resistance (MDR), high clearance rates, and other side effects because of suboptimal drug distribution and insufficient drug concentration reaching cancer cells. Innovative target drug molecules that are tailored to the injured liver cells must be developed in order to improve medication administration and drug targeting. The use of targeting ligands that have been joined to drug molecules or nanocarriers forms the basis of innovative targeting techniques. After being conjugated with the treatment method, ligands for targeting hepatocellular carcinoma cells included asialoglycoprotein, galactoside, lactobionic acid, mannose-6-phosphate, PDGF, antibodies, and aptamers.

Introduction: Diabetes mellitus (DM) is a major public health problem worldwide. Cancer is the second most common cause of death in the United States and the leading cause of death in China. There is compelling evidence that individual risk for type 2 diabetes mellitus (T2DM) is strongly influenced by genetic factors. DM and cancer may interact with one another; some kinds of cancer accompany DM, and DM can also promote cancer. Methods: An analysis was conducted of diabetes mellitus-related gene (DM-gene) expression levels in tumor and normal tissues, clinical parameters, tumor stages, mutations, copy number variations (CNVs), immune cell infiltration, survival, gene enrichment, and gene ontology annotations. Results: This analysis revealed six genes that appear to play key roles in lung cancer survival: MTMR3 (in lung adenocarcinoma [LUAD]) and COBLL1, PPARG, PPIP5K2, RREB1, and WFS1 (in lung squamous cell carcinoma [LUSC]). Conclusion: The results suggested that clinical practitioners and researchers should account for PPARG and RREB1 expression when selecting or testing chemotherapy drugs.

Background: Breast and ovarian tumors with pathogenic variants in BRCA1 or BRCA2 genes are more sensitive to poly (ADP-ribose) polymerase inhibitors (PARPi) treatment than wildtype tumors. Pathogenic variants in non-BRCA1/2 homologous recombination repair genes (HRR) also concede sensitivity to PARPi treatment. RAD50 participates in the Mre11-RAD50-Nbn (MRN) complex of the HRR pathway and plays an important role in DNA repair. Objective: The objective of this study is to evaluate whether RAD50 protein deficiency modulates the PARPi response in breast cancer cell lines. Methods: T47D breast cancer cell line was modified using small interfering RNA and CRISPR/Cas9 technology, to knockout the RAD50 gene. PARPi response (niraparib, olaparib and rucaparib alone or in combination with carboplatin), in T47D and T47D-edited clones, was evaluated by cell viability, cell cycle, apoptosis and protein expression analyses. Results: Treatment with niraparib and carboplatin exerted a synergistic effect on T47D-RAD50 deficient cells and an antagonistic effect on T47D cells parental. Cell cycle analysis demonstrated an increase in the G2/M population in cells treated with niraparib or rucaparib alone or in combination with carboplatin. T47D-RAD50 deficient cells treated with rucaparib and carboplatin exhibited twofold levels in late apoptosis, also showing differences in PARP activation. All T47D RAD50 deficient clones treated with niraparib or rucaparib combined with carboplatin, or rucaparib alone showed increased levels of H2AX phosphorylation. Conclusions: T47D RAD50 deficient cells treated with PARP inhibitors alone or in combination with carboplatin showed cell cycle arrest in the G2/M phase, leading to death by apoptosis. Thus, RAD50 deficiency may be a good biomarker for predicting PARPi response.

Aim: Enhanced Recovery After Surgery (ERAS) protocols have been proven to optimize postoperative outcomes; however, misuse of opioid analgesics can still hinder postoperative recovery due to related side effects and potential complications. Introduction: To determine if the implementation of ERAS protocol in post-chemotherapy retroperitoneal lymph node dissection (PC-RPLND) patients could help with reducing postoperative pain and opioid use. Methods: A case-control study of consecutive testicular cancer patients with indications for PCRLPND, who were offered Conventional Post-operative Management (CPM) or ERAS protocol. Outcomes of interest included Visual Analogue Scale (VAS)-assessed pain level at postoperative days 3, 7, and 30, and Morphine-Equivalent Doses (MEDs)/postoperative day. Intraoperative parameters and postoperative complications were recorded. Parametric and non-parametric tests were used for statistical analysis. Results: In total, 100 opioid-naïve PC-RPLND patients were studied. CPM and ERAS groups (36 and 64 patients, respectively) had similar demographic and baseline clinical characteristics). ERAS group patients had significantly lower blood loss (p = 0.005), blood transfusion rate (p < 0.001), and duration of the procedure (p < 0.001). Post-operative complications were comparable between groups. Nausea and bowel disorders were numerically but not statistically more frequent in the CPM group. ERAS patients had shorter mean hospital stay (5.3 ± 1.4 vs. 7.4 ± 1.6 days, p < 0.001), lower daily MEDs (4.73 ± 2.63 vs. 7.04 ± 2.29, p < 0.001), and lower VAS scores on post-operative day 7 (3.89 ± 1.07 vs. 4.67 ± 1.17, p = 0.001). Post-operative pain was similar between groups on post-operative days 3 and 30. Conclusion: Systematic implementation of ERAS protocol after PC-RPLND improves pain management, optimizes patient recovery, and prevents over-prescription of opioid analgesics.